Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Abstract

F ailure of the coronary circulation to meet the constant demands of the cardiomyocytes results in ischemic heart disease or infarction. Determining the factors that regulate coronary blood flow is, therefore, crucial for understanding pathophysiological manifestations and for the development of new therapeutic strategies. Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.3 These combined observations provide a mechanism by which arteries become relatively resistant to endogenous vasorelaxants. However, little is known about K V 7 expression levels or the functional importance of these channels in coronary arteries.Consequently, we determined the expression profiles of KCNQ genes and the functional impact of K V 7 channel modulators in left anterior descending (LAD) coronary arteries. We also ascertained whether K V 7 channels contribute to relaxations produced by adenosine, which is released rapidly after myocardial ischemia in vivo and acts as a local metabolic regulator of coronary flow. 12,13 This study demonstrates that K V 7 channels are key regulators of coronary flow at rest, and they also contribute to adenosine-mediated dilatations and the active response to ischemia. MethodsFor more complete descriptions, see the online-only Data Supplement. AnimalsThe study complies with the European Community Guidelines for the Care and Use of Experimental Animals and was approved by the Animal Ethics Screening Committee in Denmark (license number: 2010/561-1799) and by the UK Animal (Scientific Procedures) Act 1986. Male, normotensive Wistar Hannover rats and spontaneously hypertensive rats (SHRs), aged 11 to 16 weeks, were purchased from Abstract-The goal of the present study was to determine the role of KCNQ-encoded K V channels (K V 7 channels) in the passive and active regulation of coronary flow in normotensive and hypertensive rats. In left anterior descending coronary arteries from normotensive rats, structurally different K V 7.2 to 7.5 activators produced relaxations, which were considerably less in arteries from hypertensive rats and were not mimicked by the K V 7.1-specific activator R-L3. In isolated, perfused heart preparations, coronary flow rate increased in response to the K V 7.2 to 7.5 activator (S)-1 and was diminished in the presence of a K V 7 inhibitor. The expression levels of KCNQ1-5 and their known accessory KCNE1-5 subunits in coronary arteries were similar in normotensive and hypertensive rats as measured by quantitative polymerase cha...

KCNQ Channels and Novel Insights Into Coronary Perfusion

“…12 The present study supports a central role of KCNQ channels in the regulation of coronary blood flow. 10 However, given issues with drug specificity and possible heteromultimeric channel complexes, it will be critical to incorporate appropriate genetic models to establish firmly the roles of KCNQ channels in vascular function. Thus, we could find out which K V 7/KCNE channels are involved.…”

“…[3][4][5] Current data suggest important roles for K V 7 family in systemic peripheral arteries, namely myogenic response 6 and vasoregulation by vasopressin, 7 β-adrenoceptors, 8 hydrogen sulfide, and perivascular adipose tissue. 5,9 In this current issue, Khanamiri et al 10 have examined the possible role of K V 7 channels in the rat coronary circulation. They document expression of KCNQ and their known accessory KCNE1-5 subunits.…”

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

“…There are five Kv7 isoforms (Kv7.1-Kv7.5) of which Kv7.1, Kv7.4, and Kv7.5 are consistently expressed within VSM, where the predominant molecular architecture is a Kv7.4/Kv7.5 heterotetramer (2,3). Activation of Kv7 channels produces relaxation of numerous arteries (4)(5)(6)(7)(8), whereas blockade of Kv7 channels results in contraction of vessels at rest (7,(9)(10)(11) or an inhibition of endogenously derived vasorelaxations (2,(11)(12)(13). In addition, molecular reduction of Kv7.4 reduces responses to various Gs-coupled vasodilators in a number of arteries (2,11).…”

“…In addition, molecular reduction of Kv7.4 reduces responses to various Gs-coupled vasodilators in a number of arteries (2,11). Crucially, Kv7.4 abundance is reduced in various arteries from hypertensive animals (6,11,12) where relaxant responses to endogenous vasodilators are also impaired (11,12). Despite the key role of Kv7.4 channels in the regulation of VSM, and their involvement in mediating Gs-coupled vasodilator responses, the factors that regulate channel activity are poorly understood, and the signals linking Kv7.4 to Gs-receptor activation remain to be elucidated.…”

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

“…Our previous findings suggest that voltage-dependent K ϩ (K V ) channels may play an important role, but the identities of individual K V channels involved remain elusive (4,5,12,38,39). K V 7 channels are expressed in a variety of vascular smooth muscle cell types, including those from the coronary circulation (20,23). Moreover, K V 7 channels are redox sensitive, because they are activated by H 2 O 2 (13, 25).…”